tbuckley/cabot-search huggingface dataset:
Abstract 943: Modeling and dissecting of esophageal squamous cell carcinoma initiation
Authors: Kyung Pil Ko, Gengyi Zou, Yuanjian Huang, Bongjun Kim, Jie Zhang, Sohee Jun, Jae-Il Park
Journal: Cancer Research (2022)

Abstract Esophageal cancer is the 7th common cancer with the 6th highest cancer mortality rate worldwide. The 5-year survival rate of esophageal cancer is 10 ~ 25%. Esophageal cancer is mainly divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC accounts for 80% of all esophageal cancer cases and shows a poor prognosis due to a lack of symptoms at early stages. Given that early diagnosis of ESCC may lead to better outcomes, understanding the biology of ESCC initiation is imperative. To recapitulate the early events of ESCC, we employed the murine esophageal organoid (EO) system recently developed. Based on in silico analyses, we selected nine candidate genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) frequently mutated in ESCC patients. The EOs were then genetically manipulated with the combinatorial ablation of nine genes by CRISPR/Cas9 system. The EOs carrying PN (Trp53 and Notch1 KO), PC (Trp53 and Cdkn2a KO), and PCN (Trp53, Cdkn2a, and Notch1 KO) showed hyperplastic and neoplastic properties with impaired squamous cell differentiation and organoid integrity, compared to the wild-type (WT) EOs. Single-cell RNA-seq (scRNA-seq) analyses of WT, PC, PN, and PCN organoids showed the highest enrichment of ESCC cancer stem cell markers in PCN organoids. Unlike the cell lineage in WT EOs, neoplastic EOs (PC, PN, and PCN) exhibited distinct cell lineage along with multiple root cell clusters. While WT EOs failed to become neoplastic, PN, PC, and PCN EOs displayed the transforming activity in vitro and in vivo xenograft transplantation assays. Intriguingly, in allograft mouse models, while PN organoids-derived cells barely developed tumors, PC and PCN organoids-derived cells developed tumors with marked downregulation of genes related to antigen processing and presentation. These results suggest that combinatorial loss of P53, CDKN2A, and NOTCH1 play a pivotal role in ESCC neoplasia, stemness, and immune checkpoint, unveiling the biology of ESCC initiation. Citation Format: Kyung Pil Ko, Gengyi Zou, Yuanjian Huang, Bongjun Kim, Jie Zhang, Sohee Jun, Jae-Il Park. Modeling and dissecting of esophageal squamous cell carcinoma initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 943.
Abstract 928: USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model
Authors: Juntae Kwon, Hyungja Choi, Anna D. Ware, Bernadette Cecilia Morillo, Haiyang Wang, Cecil Han
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes, yet its pathological contribution to ovarian tumorigenesis remains unknown. Here, we crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse, and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer. Citation Format: Juntae Kwon, Hyungja Choi, Anna D. Ware, Bernadette Cecilia Morillo, Haiyang Wang, Cecil Han. USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 928.
Abstract 5948: Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells
Authors: Julia Ogden, Caroline Dive, Carlos Lopez Garcia
Journal: Cancer Research (2022)

Abstract Background: Lung squamous cell carcinoma (LUSC) arises from the accumulation of genetic driver alterations in bronchial basal cells. LUSC genomes lack obvious actionable mutations and present with a high degree of inter-tumor heterogeneity. Tractable, patient relevant models are needed to study LUSC pathogenesis and investigate the role of recurrent genomic alterations in driving cancer progression. Therefore, we are developing a tractable human model of LUSC progression to increase our understanding of this disease. Methods: To investigate the contribution and co-operation of frequently mutated genes (TP53 and CDKN2A) and commonly deregulated pathways (SOX2/P63, PI3K/AKT and KEAP1/NRF2 pathways) in driving LUSC progression, we genetically engineered primary human bronchial basal cells. This culminated in eight basal cell mutants harboring ubiquitous LOF alterations in TP53 and CDKN2A combined with additional pathway alterations. To assess the function of the genetic alterations in LUSC progression, we investigated proliferation using cell cycle analysis and colony forming assays. Air-liquid interface organotypic cultures were used to model histological changes in the bronchial epithelium driven by different combinations of mutations. The resultant cultures were analyzed for changes in histology indicative of LUSC progression using immunostaining to evaluate changes to epithelial cell proliferation, and expression of LUSC biomarkers. Results: Increases in proliferation were driven by inactivation of TP53, CDKN2A and PTEN, whereas SOX2 overexpression inhibited mutant basal cell proliferation. LUSC alterations also drove striking phenotypic changes in 3D organotypic cultures of the bronchial epithelium. All mutant cultures displayed thickening of the bronchial epithelium and significantly increased cellularity (p&amp;lt;0.001), indicating hyper-proliferation. SOX2 overexpression inhibited mucociliary differentiation and drove the appearance of a disordered epithelium with clear cellular and nuclear pleomorphism, indicative of high-grade premalignant lesions. Conclusions: We developed a basal cell model of recurrent LUSC genetic alterations. This approach is unique due to [1] the use of primary human cells and [2] the representation of interpatient heterogeneity and developmental stages by introducing different combinations of pathway alterations. Early results indicate that basal cells carrying cumulative alterations display increasingly complex phenotypes with features of low and high-grade premalignant lesions. Further work is required to assess the tumorigenicity of mutant cells. Citation Format: Julia Ogden, Caroline Dive, Carlos Lopez Garcia. Modeling lung squamous cell carcinoma progression using primary human bronchial basal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5948.
Abstract 6193: TWIST2 promotes tumor progression and represses myogenic differentiation in rhabdomyosarcoma
Authors: Akansha Shah, Lei Guo, Priscilla Jaichander, Kenian Chen, Karla Cano Hernandez, Lin Xu, Rhonda Bassel-Duby, Eric Olson, Ning Liu
Journal: Cancer Research (2022)

Abstract Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma of myoblast origin. RMS tumors are unable to terminally differentiate into syncytial muscle despite elevated expression of the muscle master regulators, MyoD and Myf5. Fusion-positive RMS (FP-RMS) and fusion-negative RMS (FN-RMS) have emerged as the two major RMS subtypes. The pathogenesis of FP-RMS is commonly defined by the balanced translocation of chromosomes 2 and 3 resulting in the misexpression of a chimeric PAX3/7-FOXO1 oncoprotein that derails normal differentiation pathways. However, the molecular basis of FN-RMS is poorly understood as single nucleotide variations in genes like KRAS, NRAS, and TP53 have limited recurrence (less than 10% of all patient tumors). In contrast, DNA copy number variations are highly recurrent and the genes they encode represent vulnerabilities in FN-RMS. Strikingly, we discovered that 72% of FN-RMS patient tumors harbor copy number amplifications at loci of TWIST1, TWIST2, or both, resulting in the upregulation of TWIST gene expression. We demonstrated that depletion of TWIST2 using a doxycycline inducible shRNA system caused cell cycle arrest and increased myogenic differentiation in xenograft models of FN-RMS. To interrogate whether TWIST2 can directly regulate the expression of these genes, we performed RNA-seq and ChIP-seq for TWIST2, H3K27Ac, and MYOD in TWIST2 knockdown and control FN-RMS cells. Utilizing this genome-wide data of chromatin binding, we comprehensively demonstrated that TWIST2 competes with MYOD preferentially at a subset of enhancers required for myogenic differentiation, causing repression of these loci. Interestingly, while MYOD binding is gained at myogenic loci in the absence of TWIST2, binding of MYOD is not lost at growth-promoting, oncogenic enhancers despite a decrease in their associated gene expression. This suggests that TWIST2 interacts with a different slew of transcription factors or chromatin regulators to activate gene expression. To interrogate this possibility, we are characterizing the TWIST2 protein interactome in FN-RMS cells using BioID as well as motifs enriched at TWIST2-regulated peaks. By studying TWIST2-associated pathways that affect RMS growth and differentiation, we see an opportunity to unlock novel therapeutic strategies for RMS. Citation Format: Akansha Shah, Lei Guo, Priscilla Jaichander, Kenian Chen, Karla Cano Hernandez, Lin Xu, Rhonda Bassel-Duby, Eric Olson, Ning Liu. TWIST2 promotes tumor progression and represses myogenic differentiation in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6193.
Abstract 2286: Profiling the complex rearrangement landscape of sarcoma
Authors: Sara Waise, Tom Lesluyes, Jonas Demeulemeester, Maxime Tarabichi, Nischalan Pillay, Adrienne M. Flanagan, Peter Van Loo
Journal: Cancer Research (2022)

Abstract Genomic rearrangements are key mutational processes in a number of bone and soft tissue tumors (sarcomas). These events are used for both disease classification and as prognostic and predictive biomarkers. However, the rearrangement architecture and mutational processes giving rise to many of these events remain poorly characterized. Recent data indicate that sarcomas show particularly high frequencies of complex structural rearrangements, including patterns which do not fit those of known mutational mechanisms. As the largest whole genome sequencing (WGS) dataset of sarcomas to date, the Genomics England (GE) 100,000 Genomes Project represents a unique cohort in which to examine these events. Structural variants (SVs) were identified using five SV callers (Manta, Delly, LUMPY, SvABA and GRIDSS) in WGS data from 1330 GE samples. SVs were filtered to retain only those passing the quality filter, and to remove variants present in either matched germline samples or &amp;gt;1% of a panel of normal variants. Caller performance was evaluated by comparison of distances between SV and copy number call breakpoints generated by Battenberg. SVs identified by at least two callers were taken forward as high-quality calls. Chromothriptic events, extrachromosomal DNA (ecDNA) and breakage-fusion-bridges were identified using established algorithms. In keeping with previous data, the prevalence of structural variants varies by tumor type, with particularly high numbers of SVs observed in liposarcoma and osteosarcoma. Many tumor types included notable outlier samples; these were more likely to show evidence of chromothripsis, as identified by a dedicated chromothripsis caller. Liposarcomas show the highest frequency of chromothripsis, as described previously. In addition, we have examined some tumor types at higher granularity than previously available, demonstrating directly that the prevalence of chromothripsis varies by histological subtype. For example, chromothriptic events are identified in 100% of well-differentiated liposarcomas, but less than 10% of myxoid liposarcomas. Similarly, the presence of ecDNA varies by tumor type, with the novel observation of particularly high rates in angiosarcoma. Despite recent advances in histological classification, the survival for patients with sarcoma has remained largely static for over 40 years. Determination of the mutational processes generating these rearrangements will shed light on the pathogenesis of these tumors. Citation Format: Sara Waise, Tom Lesluyes, Jonas Demeulemeester, Maxime Tarabichi, Sarcoma Genomics England Clinical Interpretation Partnership, Nischalan Pillay, Adrienne M. Flanagan, Peter Van Loo. Profiling the complex rearrangement landscape of sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2286.
Abstract 2556: The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin
Authors: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti
Journal: Cancer Research (2022)

Abstract Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de novo NEPC can rarely occur in treatment-naïve patients. Treatment-related and de-novo NEPC have different genomic alterations but share a common transcriptional profile. Investigating the tumor microenvironment, we recently found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favoring its growth, whereas are excluded by de-novo NEPC both in patients and in the transgenic TRAMP spontaneous mouse model. TRAMP mice backcrossed with MCs-deficient KitWsh mice showed increased frequency of de-novo NEPC. The frequency of de-novo NEPC similarly raised also in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting KitWsh-TRAMP mice with wild type, but not with OPN-deficient, MCs lowered the frequency of NEPC to that of untreated TRAMP mice. We found that MCs stain positive for OPN in tumor sections and in vitro cultures, but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signaling downstream toll-like receptors (TLRs). In vitro, wild type, but not OPN-/- or MyD88-/-, MCs inhibited the proliferation of NEPC cells. Also, in silico analyses showed that genes related to inflammatory response and TLRs signaling are down regulated in human and murine NEPC.Our data suggest that TLRs/MyD88/iOPN-mediated pathways induce MCs to release factor(s) able to restrain NEPC. Further studies are required to molecularly dissect this novel function of MCs, to identify actionable targets against NEPC. Citation Format: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti. The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2556.
Abstract 4042: Genomic and pharmaco-genomic profiling of pancreatic cancer using patient-derived organoids
Authors: Astrid Deschênes, Pascal Belleau, Dennis Plenker, Amber Habowski, Hardik Patel, Youngkyu Park, Hervé Tiriac, Lindsey A. Baker, Alexander Krasnitz, David A. Tuveson
Journal: Cancer Research (2022)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal common malignancies, with little improvement in patient outcomes over the past decades. We have developed a novel methodology to culture organoids from both human healthy pancreatic ductal epithelial tissues and PDAC. A collection of patient-derived organoids (PDO), grown using this protocol, numbers over 100 models to date. The 100% neoplastic purity of the organoid cultures facilitates molecular characterization that has been traditionally challenging in the pauci-cellular state of primary pancreatic tumors. These PDO open new opportunities for deep genomic and transcriptomic studies of the disease, and for individualized drug screens. Here we demonstrate that accurate predictive models of response to pharmacological treatments of PDAC can be developed using data from such screens alongside molecular profiles of the PDO. Methods: Molecular analysis of the PDO library yielded genomic and transcriptional profiles of the cultures, including those of copy number variation (CNV), mutations in the exome and mRNA expression. From these, we drew features for prediction of drug responses. Using molecular features drawn from these profiles, we developed a panel of predictive models for response to standard-of-care cytotoxic agents and a number of targeted treatments. We employed Random Forest (RF) regression as a machine-learning tool for this purpose. Results: PDO are faithful models of PDAC, whose molecular features closely resemble those of PDAC tumor specimens. Using a subset of these features, we were able to accurately learn PDO responses to cytotoxic agents: for each of the five agents considered, the predicted drug response correlated strongly (p &amp;lt; 10-7) with the observed value. A similar accuracy of prediction was achieved for a number of targeted agents. Conclusion: PDOs are a valuable resource for molecular and pharmacological characterization of PDAC, with a potential to guide clinical decisions with regard to treatment. Citation Format: Astrid Deschênes, Pascal Belleau, Dennis Plenker, Amber Habowski, Hardik Patel, Youngkyu Park, Hervé Tiriac, Lindsey A. Baker, Alexander Krasnitz, David A. Tuveson. Genomic and pharmaco-genomic profiling of pancreatic cancer using patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4042.
Abstract LB543: tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data
Authors: Xuwen Wang, Ying Xu, Yanfang Guan, Xin Yi, Jiayin Wang
Journal: Cancer Research (2022)

Abstract Estimating the status of homologous recombination deficiency (HRD) is of clinical interest because the homologous recombination-deficient cells are reported sensitive to poly-ADP ribose polymerase (PARP) inhibitors. As HRD status becomes a critical indicator, many approaches have been proposed to measure the HRD status, among which estimating HRD status from cancer sequencing data is the popular strategy, where the representative methods include HRDetect, SigMA, FoundationFocusCDx, MyChoiceHRD, etc. Although sequencing data is the same input of these bioinformatics tools, algorithms prefer different aspects. Some methods focus on germline variants in BRCA1/2 genes and somatic mutational signatures, while some others capture the genomic scars, including loss of heterozygosity (LOH), telomere allele imbalance (TAI) and large-scale state transition (LST). However, there are two major controversial points when applying these tools on clinical sequencing data. First, panel sequencing is the most popular sequencing plan in clinic, but gene panels usually carry only hundreds to a thousand genes. Thus, the panel sequencing can neither capture a large number of mutations to calculate mutational signatures, nor obtain large genomic scars, such as TAI and LST. Second, the associations between the mutations and HRD status is still unclear. Thus, scoring mutations and genomic scars is not reasonable. To solving these issues, we here proposed a machine learning-based method, called tmHRD, which estimates HRD status according to limited mutations and LOHs captured by clinical panel sequencing data. It consists of a semi-supervised learning (TRI) model and a multi-instance learning (MIL) model. The TRI model filters the false positives from mutation calls. Then, the filtered mutation calls from one patient is defined as a package, where each mutation call is an instance in the package. When training the MIL model, in each iteration, a package with known HRD status (label) is given to MIL model. MIL model calculates the correlations among instances and assigns an adjusted weight for each. Thus, the HRD status is only contributed by those mutations associated with. We tested tmHRD on several datasets obtained by the clinical trials we participated. Compared to the existing methods, tmHRD achieved better performance. The average recognition rate of tmHRD was approaching 90%, while the comparison methods show around 80%. The software package, tmHRD, is freely available at https://github.com/Sherwin-xjtu/TriMILhrd/ for academic usages only. Citation Format: Xuwen Wang, Ying Xu, Yanfang Guan, Xin Yi, Jiayin Wang. tmHRD: Accurately estimating the homologous recombination deficiency status from clinical panel sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB543.